The present invention relates to a novel process for preparing Enzalutamide which has the chemical name 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl)-2-fluoro-N-methylbenzamide and is represented by the structure:

Enzalutamide (marketed as XTANDI®) is used as an agent for treating castration-resistant prostate cancer and was approved by the U.S. Food and Drug Administration (FDA) on Aug. 31, 2012.
U.S. Pat. No. 7,709,517 (the '517 patent) describes that aniline 1 was reacted with acetone cyanohydrin 2 to lead to compound 3 in 75% yield (Scheme 1). Thiourea 5 was produced after compound 3 was reacted with commercially available isothiocyanate 4. Without isolation, thiourea 5 was subjected to hydrolysis conditions affording enzalutamide in 25% yield after column purification (acetone/DCM (5/95)). The synthetic approach is very limited for industrial application because acetone cyanohydrin 2 has been identified as an extremely hazardous chemical.

A similar approach for enzalutamide preparation was reported in PCT publication WO2011106570A1 (Scheme 2). Reaction of bromide 6 with amino acid 7 assisted by CuCl, generated compound 8 in 76% yield. Compound 8 was converted to its corresponding ester 9 in 95% yield using MeI and K2CO3. Heating a mixture containing ester 9 and isothiocyanate 4 at elevated temperature gave enzalutamide in 82% yield after recrystallization from IPA.

Another synthetic route was also reported in PCT publication WO2011106570A1 (Scheme 3). Briefly, compound 8 was coupled with aniline 10 resulting in the production of compound 11 in 36% yield. Enzalutamide was generated in 4% yield after compound 11 was heated in thiophosgene.

A concise preparation of enzalutamide was reported in Chinese patent application CN103910679A (Scheme 4). Aniline 12 was reacted with ester 13 in presence of K2CO3 providing compound 9 in 81-85% yield (Scheme 4). Heating a mixture containing ester 9 and isothiocyanate 4 at elevated temperature gave enzalutamide in 88-90% yield after recrystallization from IPA.

In view of the above, there remains a need for the development of improved processes for the preparation of enzalutamide.